Over the past decade it has became evident that the central nervous system plays a major role in mediating the actions of certain peripheral tissue-derived hormones on the skeleton. A key finding resulting from work on our lab and our collaborative work with others was that the adipose hormone, leptin, selectively targets hypothalamic neuronal populations and alters bone mass and energy metabolism via the raphae serotoninergic system (Fernandez-Galaz et al., 2002 Yadav et al., 2009), However despite the fact that leptin acts in the hind brain, the hypothalamic melanocortin system remains a key downstream effector for bone homeostasis. In particular, we found that the hindbrain action of leptin results in alteration in melanocortin tone in a manner entirely consistent with the previously described action of leptin to induce bone loss (Yadav et al., 2009). The melanocortin system consists of two distinct populations of hypothalamic neurons. One population produces proopiomelanocortin (POMC) and its key derivate, 1-melanocyte stimulating hormone (1MSH), which is the agonist for the melanocortin 4 receptor (MC4R). Activation of MC4R receptors leads to satiety and increased sympathetic tone. It is thought that this increased sympathetic tone, in turn, suppresses osteoblast function and increases osteoclast activity resulting in bone loss. The other "arm" of the melanocortin system is the population of neurons that produce neuropeptide Y (NPY), the inhibitory neurotransmitter, GABA, and Agouti- related protein (AgRP). AgRP is an inverse agonist of the MC4R, and, the AgRP/NPY/GABA neurons and tonically inhibit POMC neuronal activity (Horvath et al., 1992a,b;Cowley et al., 2001) leading to the suppression of the POMC effect on many outputs including the sympathetic nervous system. While not all hormones that affect skeletal metabolims act by modulating the melanocortin system and sympathetic outflow to the skeleton, it is our hypothesis that the activity of the melanocortin system has a critical role in regulating skeletal homeostasis. Specifically, we hypothesize that increased NPY/AgRP tone, suppresses POMC neuronal activity, reduces skeletal sympathetic tone and thereby promotes bone anabolism. Based on preliminary data which demonstrate a detrimental effect of reactive oxygen species (ROS) on NPY/AgRP neuronal function but a permissive effect of ROS on POMC neuronal firing (Andrews et al., 2008), we also predict that increasing ROS exposure of the melanocortin system during aging is a critical contributor to aging-associated bone loss and the pathogenesis of osteoporosis. PUBLIC HEALTH RELEVANCE: This grant aims to provide a novel explanation for osteoporosis in natural aging suggesting new ways of interfering with this debilitating condition To understand the etiology of osteoporosis, a devastating impairment of the bone associated with aging, it is essential that we gain better insight into the integrative regulation of bone homeostasis. We and others have contributed to the emerging critical role of various brain regions in this process. Thus, the critical analyzes of specific brain neuronal circuits in these mechanisms is important and may lead to the development of better strategies to combat impaired bone functions.